Summary Multiple Myeloma is a malignancy of the long-lived plasma cells of the bone marrow. During the last 15 years we have seen remarkable advances in both our understanding of the genomic changes associated with myeloma as well as a significant improvement in the survival of patients who are diagnosed with this disease. However the improvement in patient survival can not be attributed to the development of drugs that specifically target the genomic changes associated with myeloma. To the contrary the molecular targets of the two classes of drugs that are most active in myeloma (proteasome inhibitors and IMiDs) are not mutated in this disease and are highly expressed in normal plasma cells. Consistent with the possibility that highly active myeloma agents function in part by targeting normal plasma cell biology, proteasome inhibitors have been successfully used in preclinical models, as well as in the clinic, for the treatment of plasma cell-mediated organ transplant rejection and autoimmunity. Since plasma cells are not essential for viability as their loss can be overcome by passive transfer of immunity through the intravenous addition of immunoglobulin (e.g. IVIg), targeting normal plasma cell biology provides a novel opportunity for the treatment of plasma cell malignancies like multiple myeloma. However proteasome inhibitors are not specific to plasma cells and result in significant toxicity, therefore identifying plasma cell targets that are more selective than proteasome inhibitors could have a significant impact on the treatment of multiple myeloma. We and others have found that, CD28 and it ligand CD86 are found on normal and myeloma plasma cells and the expression of these molecules is associated with disease progression and poor prognosis. We have also previously demonstrated that CD28 provides a survival signal to myeloma cells and is required for the maintenance of normal plasma cells. We now have evidence that CD28 and CD86 are required for myeloma cell survival, even under in vitro conditions in established cell lines, suggesting that the increased expression associated with disease progression may allow for the expansion within, and the establishment of extramedullary disease outside the bone marrow micro- environment. Moreover our data suggest that CD28 and CD86 are not functioning as a simple receptor-ligand pair. We hypothesize that CD86 contributes to the survival signaling as both a ligand for CD28 as well as a signaling molecule and propose 3 Specific Aims to determine the contribution and mechanism of CD86 signaling to myeloma cell survival and tumor growth. Determining the role and mechanism of CD86 in myeloma survival is significant, as it will define a novel survival in myeloma. Importantly, since an FDA- approved agent already exists that targets this molecule, thus rapid translation of these findings to a clinical trial is possible.